Dr. Z. Leah Harris is an instructor in pediatrics at the Washington University School of Medicine. This candidate has significant clinical experience and now seeks additional basic research training in cell and molecular biology. The research in this proposal is to be conducted in the laboratory of Dr. Jonathan Gitlin which has an established track record in the study of metal metabolism in human disease. Since joining the laboratory a year ago, Dr. Harris has been involved in the characterization of a novel disorder of iron metabolism termed aceruloplasminemia and has characterized the molecular basis of this disease in several families. In this autosomal recessive disorder, patients present in adulthood with evidence of ceruloplasmin deficiency and a marked parenchymal iron accumulation resulting in progressive organ damage and morbidity. The long-term objective of these studies is to determine the cellular and molecular determinants of human iron metabolism. The specific aims of this current proposal are to develop an animal model of aceruloplasminemia by homologous recombinant knockout of the murine ceruloplasmin gene. This model will then be used to define the mechanisms of iron accumulation in aceruloplasminemia and the role of ceruloplasmin in iron metabolism. A knockout mouse will provide an essential model for elucidation of the cellular and molecular mechanisms of iron accumulation in this disease and may permit the development of new therapeutic strategies to prevent or ameliorate iron overload in a variety of human diseases. The research career development plan in this proposal is intended to allow an interim experience in the cellular and molecular biology of metal metabolism and to permit transition to an independent career. Ultimately, Dr. Harris anticipates applying these approaches towards the understanding of the biological roles of iron in human nutrition.